This invention pertains to an osmotic device containing venlafaxine. More particularly, it pertains to an osmotic device tablet that provides a controlled release of venlafaxine, and optionally an anti-psychotic agent, following a particularly advantageous release profile.
Clinical depression is a disorder characterized by low self-esteem, guilt, self-reproach, introversion, sadness, despair, sleeping disorders, eating disorders or discouragement. Depression generally causes a lower or decrease of a person""s function. Anxiety is a disorder characterized by responses to anticipation of unreal or imagined danger. It manifests itself as increased heart rate, altered respiration rate, sweating, trembling, weakness, or fatigue. Psychosis is a disorder characterized by gross impairment in reality perception as evidenced by delusions, hallucinations, markedly incoherent speech, or disorganized and agitated behavior without apparent awareness on the part of the person of the incomprehensibility of his behavior.
Major depression and anxiety occur concomitantly in more patients than either one alone. When these disorders occur together, they are associated with more severe symptoms, increased impairment of function, a longer chronic course, poorer outcome, and a higher incidence of suicide.
Antidepressants, such as venlafaxine, have been tested for the treatment of depression and symptoms of anxiety. Anti-psychotic agents, such as risperidone, are used for the treatment of psychosis. On occasion, a person suffering from depression or anxiety and psychosis will be prescribed an antidepressant agent and an anti-psychotic agent. Rather than administration of two different dosages, it would be useful in the art to have available a single dosage containing both an antidepressant and an anti-psychotic.
Venlafaxine is commercially available in an extended release capsule dosage form from Wyeth Ayerst under the trademark EFFEXOR XR(trademark). The capsule is available in 37.5, 75, and 150 mg strengths. The capsule is disclosed in U.S. Pat. No. 4,535,186 and does not contain the venlafaxine in combination with an anti-psychotic agent. Moreover, the EFFEXOR XR(trademark) formulation provides an incomplete release of venlafaxine.
Bymaster et al. (European Patent Application No. EP 0830864 A1) disclose a method, and compositions and dosage forms therefor, of treating psychoses with a combination of a serotonin uptake inhibitor and an anti-psychotic agent. Bymaster et al. do not disclose an osmotic device containing such combination nor the beneficial effects of sequential administration of the two drugs, one rapid release and the other controlled release, from a single dosage form.
Controlled release capsule dosage forms and osmotic device dosage forms are generally known by the skilled artisan to provide different release profiles. Effective therapy with antidepressants and anxiolytic agents is dependent upon a careful control of the blood plasma levels of these agents, and therefore, upon the release profiles of these agents from their respective dosage forms.
Osmotic devices and other tablet formulations are known for their ability to provide a controlled release of a wide range of drugs. Such osmotic devices and other tablet formulations are disclosed in U.S. Pat. No. 4,014,334 to Theeuwes et al., U.S. Pat. No. 4,576,604 to Guittard et al., Argentina Patent No. 234,493, U.S. Pat. No. 4,673,405 to Guittard et al., U.S. Pat. No. 5,558,879 to Chen et al., U.S. Pat. No. 4,810,502 to Ayer et al., U.S. Pat. No. 4,801,461 to Hamel et al., U.S. Pat. No. 5,681,584 to Savastano et al., U.S. Pat. No. 3,845,770, U.S. Pat. No. 6,004,582 to Faour et al., and Argentina Patent No. 199,301, the entire disclosures of which are hereby incorporated by reference.
These references, however, do not disclose osmotic devices that provide the specific plasma profiles or release profiles for venlafaxine (VFX), and an optional anti-psychotic agent, that the present invention provides. Moreover, the prior art does not disclose an osmotic device containing a combination of venlafaxine with an anti-psychotic agent, and generally wherein the venlafaxine and anti-psychotic agent are delivered according to specific release profiles that are advantageous over known formulations.
In one aspect, the present invention provides an osmotic device comprising:
a core comprising a therapeutically effective amount of venlafaxine and at least one osmotic agent or osmopolymer; and
a semipermeable membrane surrounding the core and having a passageway there through;
wherein the core provides a controlled release of VFX, and at least 80% of the VFX is released within 13 hours after exposure of the osmotic device to an aqueous solution.
Another aspect of the present invention provides an osmotic device for the delivery of VFX and an anti-psychotic agent comprising:
a core comprising a therapeutically effective amount of venlafaxine and at least one osmotic agent or osmopolymer;
a semipermeable membrane surrounding the core and having a passageway there through; and
an external coat comprising a therapeutically effective amount of an anti-psychotic agent;
wherein the core provides a controlled release of VFX, and at least 80% of the VFX is released within 13 hours after exposure of the osmotic device to an aqueous solution, and the external coat provides a rapid release of the anti-psychotic agent, and at least 75% of the anti-psychotic agent is released within 1 hour after exposure of the osmotic device to an aqueous solution.
In some embodiments, the external coat is applied by spray coating or compression coating. By spray coating rather than compression coating the external coat, a thinner external coat, and therefore a smaller osmotic device, is formed.
Another aspect of the invention provides a method of treating depression, anxiety and/or psychosis in a mammal, the method comprising the step of administering an osmotic device which provides a controlled release of VFX from its core and a rapid release of an anti-psychotic agent from an external coat, wherein at least 75% of the anti-psychotic agent is released within about 40 minutes, and at least about 60% of the VFX is released within about 12 hours after administration.
In other embodiments, the osmotic device provides: a) a VFX release profile similar to that shown in FIG. 1; or b) a VFX plasma profile similar to that shown in FIGS. 2 or 4. In still other embodiments, the release of VFX and/or the anti-psychotic agent has a delayed onset.
In even other embodiments, the anti-psychotic agent is selected from the group consisting of risperidone, olanzapine, clozapine, sertindole, ziprasidone, quetiapine, sulpiride, pimozide, clothiapine, molindone, loxapine, trifluoperazine, haloperidol, flupenthixol, chlorpromazine, chlorprothixene, clopenthixol, droperidol, perphenazine, fluphenazine, lithium, mesoridazine, spiperone, promazine, prochlorperazine, thioridazine, thiothixene, triflupromazine, and raclopride.
In yet other embodiments, the following anti-psychotic agents are administered in the indicated doses: a) risperidonexe2x80x945 to 10 mg per day; b) olanzapinexe2x80x945 to 20 mg, 0.25-50 mg, 1-30 mg, or 1-25 mg per day; c) clozapinexe2x80x94100 to 400 mg, 12.5-900 mg, or 150-450 mg per day; d) sertindolexe2x80x9415 to 20 mg per day or 0.0001 to 1.0 mg/kg of body weight per day; e) ziprasidonexe2x80x9480 to 160 mg, 5 to 500 mg or 50 to 100 mg per day; f) quetiapinexe2x80x94150 to 600 mg or 1.0-40 mg/kg of body weight per day; g) sulpiridexe2x80x9450 to 100 mg per day; h) pimozidexe2x80x942 to 4 mg per day; or i) clothiapinexe2x80x9440 mg per day.
The venlafaxine, as either its free base or salt form, will be administered once daily in doses ranging form about 10 to 150 mg, 25 to 125 mg, 150 to 300 mg, or 10-500 mg.
The osmotic device generally delivers the anti-psychotic agent to the upper GI tract and the venlafaxine to the middle to lower GI tract.
Other features, advantages and embodiments of the invention will become apparent to those skilled in the art by the following description, accompanying examples.